Alzheimer?s disease (AD) and Alzheimer?s disease related dementia (ADRD) are the most common cause of dementia, affecting 3?11% of the United States elderly. On the other hand, the estimated incidence of prenatal alcohol exposure (PAE)-induced mental disability or disease is 10 per 1000 live births. Although theoretically PAE-induced mental diseases are preventable, the prevalence of maternal alcohol consumption during pregnancy has been reported to be as high as 10%-16.3%, together with the increased life expectancy by 8-10 years in USA during the last 50 years, making the evaluation of PAE on cognitive degeneration and its mechanistic studies extremely important. It is well accepted that AD/ADRD arise through interactions between genetic and environmental factors, among which PAE has been considered an external, environmental insult to the brain at the prenatal stage. As a logical continuation of the parent R01 project, which studies rats free of AD/ADRD risk mutations, in the current proposal both outbred Sprague Dawley (SD) rats, and inbred F344 transgenic (tg) AD rats, which express mutant human amyloid precursor protein (APPsw) and presenilin 1 (PS1?E9) genes, will be explored in vivo and in vitro to test whether the PAE-facilitated degeneration is observed on subjects either lacking and possessing AD risk genes. Our parent R01 grant, titled ?synaptic adaptations induced by prenatal alcohol exposure?, focused on the PAE-induced synaptic and behavioral alterations at the adolescent stage. The current proposal will extend these assessments into adult stage and beyond. Our hypothesis is that PAE will accelerate neuronal degeneration in both SD and tgF344 AD rats at behavioral, synaptic, and molecular levels. Atrophy of the nucleus accumbens (NAc) has been found in mild cognitive impairment (MCI, indicating high risk of developing AD/ADRD) and AD human cases. More importantly, smaller volume of the NAc, considered as a predictor of AD onset within 2 years, is associated with increased risk of progression from MCI to AD. Two well- investigated molecular events in AD subjects, including extracellular deposition of amyloid-? peptides and intracellular formation of neurofibrillary tangles have been detected in the NAc. Thus, the NAc will be explored as a novel brain region involved in AD/ADRD and synaptic transmission in the NAc will be analyzed in the context of AD/ADRD as a novel aspect different from the traditional AD hallmark peptide/protein analysis in hippocampus and cortex. Our research goals are to evaluate the effects of PAE on the degenerative process in SD rats and tgF344 AD rats, in an age-dependent manner, by measuring learning and memory phenotypes and synaptic degeneration in the NAc.